Summary Treatment-resistant hypertension (RHTN) was defined as persistent elevation of blood pressure above goal despite concurrent use of 3 antihypertensive agents, each of unique class with a diuretic included among the treatment regimen, and with all drugs at target dose. RHTN occurs in a fifth of patients with either at least three atherosclerotic risk factors or established disease, and 10% of these patients are refractory to hypertensive treatment even after treatment with 5-6 different classes of antihypertensive drug. RHTN is characterized by uncontrolled hemodynamic changes and vascular dysfunction, and is correlated with a variety of coronary artery disease risk factors. Despite major advances in the treatment of coronary and vascular diseases in the last three decades, physicians are having difficulties to achieve controlled blood pressure in RHTN patients, perhaps due to the lack of therapeutics that can actively improve endothelial functions. As a result, hypertension is unchecked and continues to damage vascular functions every day in millions of RHTN patients, and these patients have a significantly increased risk of all-cause mortality and cardiovascular mortality when compared with those with controlled hypertension. Clearly, novel strategies that can actively improve vascular functions in RHTN patients are much needed. Recent advances have shown that the signaling of a group of vascular receptors, CLR/RAMP receptors, and their cognate ligands (i.e., adrenomedullin [ADM], calcitonin gene-related peptides [?- and ?-CGRP] and intermedin/adrenomedullin 2 [IMD/ADM2]) is essential for vascular development during embryogenesis and throughout adulthood. Consistently, these peptide hormones have been shown to improve angiogenesis, vasculogenesis and endothelial barrier functions in animals, and prevent hemodynamic disturbances in humans. Importantly, we have recently developed a group of peptidomimetics that exhibit superior bioactivity when compared to native ligands. Based on this novel finding, here we propose to develop a poly(DL-lactic-co- glycolic acid)(PLGA)-based superagonist nanoparticle for improving vascular compliance, endothelial integrity, and vasotone in RHTN patients. In this proof-of-concept study, we will identify an optimal nanoparticle formulation for the slow-release of the selected drug candidate in Aim 1. In Aim 2, we will investigate the efficacies of the formulated superagonist nanoparticle in reducing hypertension and cardiac hypertrophy in spontaneous hypertensive rats. Successful completion of this Phase I SBIR proposal will provide us novel drug candidates that are ready for formal preclinical development.